Is NDUFS8 p.Pro85= (c.255G>A) pathogenic?

NDUFS8 p.Pro85= (c.255G>A) is classified Conflicting classifications of pathogenicity in NDUFS8 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-01). Rare (popmax 0.355%, nfe); Associated with mitochondrial complex I deficiency, nuclear type 1.

What condition is associated with NDUFS8 p.Pro85= (c.255G>A)?

NDUFS8 p.Pro85= (c.255G>A) is associated with mitochondrial complex I deficiency, nuclear type 1, Leigh syndrome (ClinVar).

How common is NDUFS8 p.Pro85= (c.255G>A) in the general population?

NDUFS8 p.Pro85= (c.255G>A) is rare (popmax 0.355%, nfe) (gnomAD).

NDUFS8 p.Pro85=

c.255G>A · rs144125742 · VCV378258

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.355%, nfe)

Conditions

mitochondrial complex I deficiency, nuclear type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -16
Overall
CADD	1.683	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.355% European (non-Finnish) · 4,191/1,179,690 alleles

Filtering AF 0.346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.343%

Overall 0.337% 5,434/1,612,588 alleles · rare exomes 4,926/1,460,298 · genomes 508/152,290 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.44%	69
Amishnot grpmax-eligible	0.548%	182
European (non-Finnish)grpmax	0.355%	281
Remaining individualsnot grpmax-eligible	0.243%	411
Admixed American	0.187%	535
African / African-American	0.0773%	1,294
Middle Eastern	0.0165%	6,062
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,784
South Asian	0.0022%	45,505

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NDUFS8
Protein: p.Pro85=
Coding: c.255G>A
MANE Select: NM_002496
dbSNP: rs144125742
Type: single nucleotide variant
Location: chr11:68033166 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI 0.03 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.73 · 7 PDB
Residue 85: a UniProt-annotated variant site (in mc1dn2; uncertain significance); a turn

Full NDUFS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex I deficiency, nuclear type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leigh syndrome

Similar variants

NDUFS8 p.Pro85Leu Pathogenic same residue
NDUFS8 p.Met147Ile Likely pathogenic ★★ same condition
NDUFS8 c.199+5G>A Uncertain significance ★★ same condition
NDUFS8 p.Ala200Thr Uncertain significance ★★ ⚠ same condition
NDUFS8 p.Arg18Leu Uncertain significance ★★ ⚠ same condition
NDUFS8 p.Gly192Arg Uncertain significance ★★ ⚠ same condition
NDUFS8 p.Pro22Ser Uncertain significance ★★ ⚠ same condition
NDUFS8 c.199+15T>G Benign/Likely benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ndufs8-p-pro85 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown